It has been demonstrated that the T cell proliferative response to Con A and the T cell dependent antibody responses to the soluble antigens TNP-KLH, TNP-T,G-(A-L), and TNP-Nuclease require the participation of accessory cells. This subpopulation of spleen cells has been shown to be glass adherent, radioresistant, non-T, non-B and to express Ia (I region associated) determinants encoded in I-A and I-E/C. In addition, I-A and I-E positive cells within the splenic adherent cell population are the predominant stimulators of the one way murine mixed lymphocyte response when responder and stimulator cells differ either at H-2 or the Mls locus. Studies designed to analyze the functional importance of specific determinants on Ia molecules have been initiated employing a battery of monoclonal anti-I-E reagents specific for different epitopes on the same I-E product molecule. Inhibition studies suggest that different domains on Ia molecules have differential functional importance.